Dipropylacetic acid (valproic acid) is a common broad spectrum anti-convulsant drug effective in the prevention of seizures. In rare cases, there have been incidents of hepatotoxicity experienced by patients being treated with the drug. As a result, there is an increasing level of interest in the relationship of hepatic toxicity with valproic acid and its metabolites.
The primary routes in the extensive metabolism of valproic acid (VPA) are mitochrondrial .beta.-oxidation and microsomal glucuronidation. The hepatotoxicity of VPA is mediated through the unsaturated metabolites: (A) 2-propylpent-4-enoic acid (4-en-VPA), 2-propylpent-3-enoic acid (3-en-VPA) and 2-propylpenta-2,4-dienoic acid (2,4-dien-VPA), which are formed after omega and omega-1 oxidation of VPA in the endoplasmic reticulum, and (B) 2-propylpent-2-enoic acid (2-en-VPA), which is formed by .beta.-oxidation in the mitochondria. As is the case with the well-characterized hepatotoxins, hypoglycin A and pent-4-enoic acid, excessive amounts of these metabolites are thought to primarily affect mitochondrial function by inhibition of one or more enzymes in the .beta.-oxidation sequence, and/or depletion or sequestration of either carnitine or coenzyme A, or both. The inhibition of .beta.-oxidation leads to diversion of fatty acids, first producing dicarboxylicaciduria, then microvesicular steatosis, while also affecting mitochondrial energetics and processes dependent thereupon. Mitrochondrial inhibition and depletion of glycogen stores can ultimately lead to enhanced production of the en-VPA metabolites, creating a vicious cycle leading to fulminant hepatitis and death. In the majority of patients receiving valproic acid, the extent of formation of these metabolites is minimal; however, in some patients, particularly those receiving concomitant medication capable of inducing enzymes in the endoplasmic reticulum, the amount of the metabolites is greater, causing transient but reversible changes in hepatic function indicators. In rare cases, due to excessive levels of the metabolites or due to individual susceptibility caused by genetic mitochondrial defects, defects in glucuronidation, trauma, hepatotoxins or other exacerbating circumstances, compensation for the presence of the metabolites does not occur, and severe hepatotoxicity ensues.
In any event, the availability of compounds which do not exhibit hepatotoxicity is desirable.